Suppression of Cytokine-Dependent Human T-Cell Proliferation by Intravenous Immunoglobulin

doi:10.1006/clin.1994.1186

Clinical Immunology and Immunopathology

Volume 73, Issue 2, November 1994, Pages 180-186

Clinical Immunology ...

https://doi.org/10.1006/clin.1994.1186 Get rights and content

Abstract

Human intravenous immunoglobulin (hIVIG) modifies the course of numerous immune-mediated diseases, but its specific mode of action remains unknown. In order to delineate possible immunoregulatory mechanisms, we studied the effects of hIVIG on the in vitro proliferation of human T cells. Cells from normal donors were stimulated with anti-CD3 antibody, tetanus toxoid antigen or the combination of a phorbol ester/ionomycin (P/I) and incubated with increasing concentrations of hIVIG (1 mg/ml to 10 mg/ml) for three to seven days. Addition of hIVIG inhibited anti-CD3 and tetanus but not P/I-induced proliferation in a dose-dependent manner. Addition of exogenous IL-2 to the cultures overcame the inhibitory effect of hIVIG; addition of IL-4 was ineffective. To further define the effect of hIVIG on specific cell populations, competent, purified T cells were stimulated with anti-CD3 or phorbol ester for three days in the presence of hIVIG. Addition of hIVIG blocked anti-CD3 and phorbol ester-induced stimulation of competent T cells. In cultures of competent T cells, either IL-2 or IL-4 was successful in reversing the hIVIG-induced inhibition. In these cultures, hIVIG also significantly prevented the synthesis/secretion of both IL-2 and IL-4 in PDB-stimulated competent T cells. Taken together, these data suggest that one mechanism of action of hIVIG may be through its interference with cytokine-dependent T-cell proliferation.

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Intravenous immunoglobulin (IVIG) is commonly used to treat severe COVID-19, although the clinical outcome of such treatment remains unclear. This study evaluated the effectiveness of IVIG treatment in severe COVID-19 patients.
This retrospective multicentre study evaluated 28-day mortality in severe COVID-19 patients with or without IVIG treatment. Each patient treated with IVIG was matched with one untreated patient. Logistic regression and inverse probability weighting (IPW) were used to control confounding factors.
The study included 850 patients (421 IVIG-treated patients and 429 non-IVIG-treated patients). After matching, 406 patients per group remained. No significant difference in 28-day mortality was observed after IPW analysis (average treatment effect (ATE) = 0.008, 95% CI –0.081 to 0.097, p 0.863). There were no significant differences between the IVIG group and non-IVIG group for acute respiratory distress syndrome, diffuse intravascular coagulation, myocardial injury, acute hepatic injury, shock, acute kidney injury, non-invasive mechanical ventilation, invasive mechanical ventilation, continuous renal replacement therapy and extracorporeal membrane oxygenation except for prone position ventilation (ATE = –0.022, 95% CI –0.041 to –0.002, p 0.028).
IVIG treatment was not associated with significant changes in 28-day mortality in severe COVID-19 patients. The effectiveness of IVIG in treating patients with severe COVID-19 needs to be further investigated through future studies.
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Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects.
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Citation Excerpt :
However, because IVIg contains anti-mouse IgG reactivity [32], it can be speculated that at least some IVIg binds to anti-CD3 and anti-CD28 on the beads. This finding is of importance considering that anti-CD3 antibodies, in combination or not with anti-CD28, have been commonly used to determine the effect of IVIg on T cells [25,26,33]. In these studies, the authors concluded that IVIg inhibits the function of activated T cells (proliferation, cytokine secretion or expression of activation markers such as CD25 or CD69).
Clinical observations in patients treated with IVIg revealed significant modulations in T cell populations and functions. However, it is unclear whether IVIg acts directly on activated T cells to suppress their functions. To clarify the exact mechanism of IVIg action, we studied its effect on T cells activated using anti-CD3/CD28 microbeads to mimic stimulatory signals provided by accessory cells. We report here that IVIg reduces T cell proliferation and cytokine secretion by interfering with the ability of anti-CD3/CD28 microbeads to deliver activating signals to T cells. We further show that the interference occurs between IVIg and anti-CD3/CD28 microbeads and does not involve T cells. In conclusion, our work suggests that T cells are not a direct target of IVIg and that the modulation of T cell populations and functions observed in treated patients is the indirect consequence of a direct effect of IVIg on accessory cells.
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Regular ArticleSuppression of Cytokine-Dependent Human T-Cell Proliferation by Intravenous Immunoglobulin

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Regular Article
Suppression of Cytokine-Dependent Human T-Cell Proliferation by Intravenous Immunoglobulin